Montelukast is the International Non-proprietary Name (INN) for (R)-(E)-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid, and CAS RN 158966-92-8.
Montelukast monosodium salt (CAS RN 151767-02-1) of formula Ia
belongs to a group of drugs known as leukotriene antagonists. It is an orally active compound, which binds with high affinity and selectivity to CysLT1 receptor. Montelukast monosodium salt is currently used in the treatment of asthma, inflammation, angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis and allograft rejection.
The preparation of montelukast sodium salt was first described in EP 480717 (Example 161). Later on, an alternative process was described for the preparation of a montelukast intermediate in EP 500360. However, these processes are not particularly suitable for industrial-scale application due to the use of solvents such as dichloromethane, reagents such as hydrazine, and temperatures below −40° C. In addition, such processes require tedious chromatographic purifications of some intermediates and/or final products, and yields of final product are low.
Among the strategies for the preparation of montelukast, processes comprising the formation of amine salts of montelukast which are subsequently converted into its sodium salt have also been described. Some of these processes, as described below, comprise the purification of the dicyclohexylamine salt of montelukast:

Thus, for example, European Patent Application EP 737186 (whose United States equivalent is U.S. Pat. No. 5,614,632), discloses a process to prepare a crystalline form of montelukast sodium from the dicyclohexylamine salt of montelukast. This process is hardly applicable on an industrial scale since a highly flammable base (n-butyl lithium) and reaction temperatures below −10° C. are used. In addition, an impurity, which is derived from dehydration of the tert-butanol group, is formed during the preparation of montelukast and its removal becomes very difficult. Moreover, the purification steps via the dicyclohexylamine salt are very time consuming and comprise seeding of montulekast and dicyclohexylamine solution in toluene or ethyl acetate, and subsequent addition of heptane or hexane respectively.
In document WO 06/008751 (whose United States equivalent is United States Publication No. 2009/143590), another process is described for obtaining montelukast sodium salt which comprises converting montelukast into its dicyclohexylamine salt. However, this process also requires seeding of the solution, and a very long period of time (more than one day) is needed for crystallization of the dicyclohexylamine salt.
Moreover, purification via the dicyclohexylamine salts has also been applied to intermediates which are subsequently converted into montelukast.
Thus, documents WO 06/008751 (whose United States equivalent is United States Publication No. 2009/143590), and WO 07/004237 describe the preparation of montelukast through the formation of a dicyclohexylamine salt of the methyl ester intermediate of formula:

However, these processes show the same drawbacks as those described for the formation of dicyclohexylamine salts over montelukast acid.
Therefore, due to the difficulty in purifying montelukast and its intermediates, the provision of alternative processes for preparation of montelukast, it is of great interest, particularly if they are easily industrializable.